Gene-by-Smoking Interaction and Risk of Atherosclerosis

描述（由申请人提供）：虽然吸烟是动脉粥样硬化血管疾病的一个公认的潜在风险因素，但个体对吸烟的易感性差异很大，表明存在基因组变异等修饰因素。参与致突变烟草烟雾化合物的活化和解毒、氧化应激和DNA损伤的几种关键酶在心脏和脉管系统的组织中表达，并且代表烟草诱导的病理学的机制途径。这些酶中的许多具有已知功能效应的常见多态性（在人群中大于或等于10%的患病率）。虽然仅限于少数酶，并受到设计缺陷的阻碍，但少数研究表明，烟草烟雾的酶激活和解毒改变了与吸烟相关的某些心血管结局的风险。这项研究的主要目的是评估常见的遗传多态性，结合暴露于烟草烟雾，可能会改变动脉粥样硬化及其临床后遗症的风险。 在参与激活、解毒、氧化应激和DNA修复途径的19个基因中，根据其患病率和功能意义、相关组织中的表达、既往研究中的评价和生物相容性选择平均6个多态性，作为社区动脉粥样硬化风险（ARIC）研究的辅助研究进行评价。在这个自1987-89年以来积极随访的15，792名男性和女性的良好特征的双种族队列中，（随访完整性96%），将以病例-队列/病例-对照模式研究量化亚临床动脉粥样硬化和经验证的临床动脉粥样硬化事件的五个终点：突发冠心病、颈动脉粥样硬化、外周动脉疾病、突发中风和MRI检测的脑梗死。这项研究旨在研究DNA序列多态性如何促进或抑制吸烟的致动脉粥样硬化作用和临床事件的风险，并为遗传变异在环境损伤和毒物反应中的作用提供新的知识。研究结果预计将具有临床和公共卫生意义。

DESCRIPTION (provided by applicant): While cigarette smoking is a well-established and potent risk factor for atherosclerotic vascular disease, individual susceptibility to smoking varies considerably, suggesting modifiers such as genomic variation. Several key enzymes involved in the activation and detoxification of mutagenic tobacco smoke compounds, oxidative stress, and DNA damage are expressed in the tissues of the heart and vasculature and represent mechanistic pathways for tobacco-induced pathology. Many of these enzymes have common polymorphisms (greater than or equal too 10% prevalence in the population) with known functional effects. Although restricted to a few enzymes and hampered by shortcomings in design, a small number of studies have suggested that enzymatic activation and detoxification of tobacco smoke modifies the risk of certain cardiovascular outcomes associated with cigarette smoking. The main goal of the proposed study is to evaluate common genetic polymorphisms that, in combination with exposure to tobacco smoke, may modify the risk of atherosclerosis and its clinical sequelae. An average of six polymorphisms, selected on the basis of their prevalence and functional significance, expression in relevant tissues, evaluation in previous studies and biologic plausibility, within 19 genes involved in activation, detoxification, oxidative stress, and DNA repair pathways will be evaluated as an ancillary study to the Atherosclerosis Risk in Communities (ARIC) study. In this well-characterized, bi-ethnic cohort of 15,792 men and women under active follow-up since 1987-89 (completeness of follow-up 96%), five endpoints quantifying subclinical atherosclerosis and validated clinical atherosclerotic events will be studied in case-cohort/case-control mode: incident coronary heart disease, carotid atherosclerosis, peripheral arterial disease, incident stroke, and MRI-detected cerebral infarcts. The proposed investigation is well designed to study how DNA sequence polymorphisms can promote or inhibit the atherogenic effects of smoking and the risk of clinical events, and to contribute new knowledge on the role of genetic variation in the response to environmental insults and toxicants. The findings are expected to be of clinical and public health significance.